Effects of Angiotensin Receptor-Neprilysin Inhibitors (ARNIs) on the Glucose and Fat Metabolism Biomarkers Leptin and Fructosamine.

(1) Background: Heart failure with reduced ejection fraction (HFrEF) remains a major health burden. Angiotensin-Receptor-Neprilysin-Inhibitors (ARNIs) are an established HFrEF therapy which increases natriuretic peptide levels by inhibiting neprilysin. Leptin is a lipid metabolism parameter, which is also involved in glucose metabolism and is suggested to correlate with HF burden. While the hormone also seems to interact with neprilysin, potential associations with ARNI therapy have not been investigated yet. (2) Methods: To study this issue, we measured levels of leptin and fructosamine in consecutive 72 HFrEF patients before initiation of ARNI therapy and 3-6 months after initiation of therapy in two European centers. Biomarker levels were correlated with clinical parameters including ejection fraction, LVEF, and NYHA class. (3) Results: During a follow-up of up to 6 months, clinical parameters improved significantly (LVEF: 30.2 ± 7.8% to 37.6 ± 10.0%, (p < 0.001) and a significant improvement of the mean NYHA class with initial 32 patients in NYHA III or IV and 8 patients in NYHA class III/IV during the follow up (p < 0.001). The initial NT-proBNP levels of 2251.5 ± 2566.8 pg/mL significantly improved to 1416.7 ± 2145 pg/mL, p = 0.008) during follow up. ARNI therapy was also associated with an increase in leptin levels (17.5 ± 23.4 µg/L to 22.9 ± 29.3, p < 0.001) and furthermore, affected glucose metabolism indicated by elevation of fructosamine values (333.9 ± 156.8 µmol/L to 454.8 ± 197.8 µmol/L, p = 0.013). (4) Conclusion: while in the early phase of therapy, ARNI promotes clinical improvement of HFrEF, and it also seems to affect fat and glucose parameters, indicating significant metabolic implications of this therapy regime.

Differences of Hemogram Parameters and Their Ratios among Patients with Takotsubo Syndrome, Acute Coronary Syndrome and Healthy Individuals.

Introduction: Takotsubo cardiomyopathy (TTC) and acute coronary syndrome (ACS) are clinically indistinguishable from each other. Although therapeutically redundant, coronary angiography remains indispensable for differential diagnosis. Methods: In our study, we compared hemogram parameters and their ratios in 103 patients presenting with undiagnosed chest pain. Blood was drawn at baseline in 40 patients with TTC, 63 patients with ACS, and 68 healthy controls ((Ctrl) no coronary artery disease or signs of heart failure). Results: Peripheral lymphocyte counts were significantly depressed in TTC and ACS patients when compared to the Ctrl. Consequently, all three investigated hemogram ratios were significantly elevated in patients with ACS or TTC (NLR: TTC: median 3.20 vs. ACS: median 3.82 vs. Ctrl: median 2.10, p < 0.0001; BLR: median 0.02 vs. ACS: median 0.00 vs. Ctrl: median 0.00, p < 0.0001; MLR: median 0.37 vs. ACS: median 0.44 vs. Ctrl: median 0.28, p < 0.0001). Of note, BLR was only significantly elevated in patients with TTC, and not in patients with ACS (ACS vs. Ctrl p = 0.183). Conclusion: Basophil count and BLR are significantly increased in TTC patients when compared to ACS and may, therefore, be helpful in the distinction of TTC from ACS. Whereas NLR might be useful to differentiate ACS from controls. Elevated basophil counts and BLR in TTC patients are interesting findings and may confirm speculations about the partly unexplained pathophysiology.

Analysis of Selected Cardiovascular Biomarkers in Takotsubo Cardiomyopathy and the Most Frequent Cardiomyopathies.

Introduction: Among the causes of de novo diagnosed cardiomyopathy, Takotsubo cardiomyopathy (TTC) plays a minor role, with an occurrence of 50,000-100,000 cases per annum in the United States. In clinical practice, a differentiation of a TTC toward an ischemic cardiomyopathy (ICMP) or a dilatative cardiomyopathy (DCMP) appears to be challenging, especially in a subacute setting or in atypical types of TTC. Methods: To investigate this issue, we analyzed serum levels of sST2, GDF-15, suPAR, HFABP, and clinical parameters including echocardiography in 51 patients with TTC, 52 patients with ischemic cardiomyopathy (ICMP) and 65 patients with dilated cardiomyopathy (DCMP). Results: sST-2 seemed to be the most promising biomarker for prediction of a TTC in differential diagnosis to an ICMP (AUC: 0.879, p = < 0.001, Cut off values: 12,140.5 pg/ml) or to a DCMP (AUC: 0.881, p = < 0.001, cut off value: 14521.9 pg/ml). GDF-15 evidenced a slightly lower AUC for prediction of a TTC in differential diagnosis to an ICMP (AUC: 0.626, p = 0.028) and to a DCMP (AUC: 0.653, p = 0.007). A differential diagnostic value was found for H-FABP in the prediction of a DCMP compared to TTC patients (AUC: 0.686, p = < 0.001). In propensity score matching for left ventricular ejection fraction, sex, and cardiovascular risk factors, differences in the plasma levels of sST2 and H-FABP in the matched cohort of TTC vs. DCMP remained statistically significant. In the matched cohort of TTC vs. ICMP, differences in sST2 also remained statistically significant Conclusion: As medical therapy, long term prognosis, interval of follow-ups, rehabilitation program and recommendations differ completely between TTC and ICMP/DCMP, biomarkers for differential diagnosis, or rather for confirmation of diagnosis, are warranted in cases of cardiomyopathies with unsure origin. sST-2, GDF-15 and H-FABP might facilitate the classification.

Cardiac Arrhythmias in Survivors of Sudden Cardiac Death Requiring Impella Assist Device Therapy.

In this retrospective single-center trial, we analyze 109 consecutive patients (female: 27.5%, median age: 69 years, median left ventricular ejection fraction: 20%) who survived sudden cardiac death (SCD) and needed hemodynamic support from an Impella assist device between 2008 and 2018. Rhythm monitoring is investigated in this population and associations with hospital survival are analyzed. Hospital mortality is high, at 83.5%. Diverse cardiac arrhythmias are frequently registered during Impella treatment. These include atrial fibrillation (AF, 21.1%) and ventricular tachycardia (VT, 18.3%), as well as AV block II°/III° (AVB, 7.3%), while intermittent asystole (ASY) is the most frequently observed arrhythmia (42.2%). Nevertheless, neither ventricular nor supraventricular tachycardias are associated with patients' survival. In patients who experience intermittent asystole, a trend towards a fatal outcome is noted (p = 0.06). Conclusions: Mortality is high in these severely sick patients. While cardiac arrhythmias were frequent, they did not predict hospital mortality in this population. The hemodynamic support of the pump seems to counterbalance the adverse effects of these events.

Impella use in real-world cardiogenic shock patients: Sobering outcomes.

BACKGROUND: Critically ill patients with cardiogenic shock could benefit from ventricular assist device support using the Impella microaxial blood pump. However, recent studies suggested Impella not to improve outcomes. We, therefore, evaluated outcomes and predictors in a real-world scenario. METHODS: In this retrospective single-center trial, 125 patients suffering from cardiac arrest/cardiogenic shock between 2008 and 2018 were analyzed. 93 Patients had a prior successful cardiopulmonary resuscitation. The primary endpoint was hospital mortality. Associations of covariates with the primary endpoint were assessed by univariable and multivariable logistic regression. Adjusted odds ratios (aOR) and optimal cut-offs (using Youden index) were obtained. RESULTS: Hospital mortality was high (81%). Baseline lactate was 4.7mmol/L [IQR = 7.1mmol/L]. In multivariable logistic regression, only age (aOR 1.13 95%CI 1.06-1.20; p<0.001) and lactate (aOR 1.23 95%CI 1.004-1.516; p = 0.046) were associated with hospital mortality, and the respective optimal cut-offs were >3.3mmol/L and age >66 years. Patients were retrospectively stratified into three risk groups: Patients aged ≤66 years and lactate ≤3.3mmol (low-risk; n = 22); patients aged >66 years or lactate >3.3mmol/L (medium-risk; n = 52); and patients both aged >66 years and lactate >3.3mmol/L (high-risk, n = 51). Risk of death increased from 41% in the low-risk group, to 79% in the medium risk group and 100% in the high-risk group. The predictive abilities of this model were high (AUC 0.84; 95% 0.77-0.92). CONCLUSION: Mortality was high in this real-world collective of severely ill cardiogenic shock patients. Better patient selection is warranted to avoid unethical use of Impella. Age and lactate might help to improve patient selection.

The Diagnostic and Therapeutic Value of Multimarker Analysis in Heart Failure. An Approach to Biomarker-Targeted Therapy.

Background: Heart failure is a pathophysiological state, which is still associated with high morbidity and mortality despite established therapies. Diverse well-known biomarkers fail to assess the variety of individual pathophysiology in the context of heart failure. Methods: An analysis of prospective, multimarker-specific therapeutic approaches to heart failure based on studies in current literature was performed. A total of 159 screened publications in the field of biomarkers in heart failure were hand-selected and found to be eligible for this study by a team of experts. Results: Established biomarkers of the inflammatory axis, matrix remodeling, fibrosis and oxidative stress axis, as well as potential therapeutic interventions were investigated. Interaction with end organs, such as cardio-hepatic, cardio-renal and cardio-gastrointestinal interactions show the complexity of the syndrome and could be of further therapeutic value. MicroRNAs are involved in a wide variety of physiologic and pathophysiologic processes in heart failure and could be useful in diagnostic as well as therapeutic setting. Conclusion: Based on our analysis by a biomarker-driven approach in heart failure therapy, patients could be treated more specifically in long term with a consideration of different aspects of heart failure. New studies evaluating a multimarker - based therapeutic approach could lead in a decrease in the morbidity and mortality of heart failure patients.

Classic and Novel Biomarkers as Potential Predictors of Ventricular Arrhythmias and Sudden Cardiac Death.

Sudden cardiac death (SCD), most often induced by ventricular arrhythmias, is one of the main reasons for cardiovascular-related mortality. While coronary artery disease remains the leading cause of SCD, other pathologies like cardiomyopathies and, especially in the younger population, genetic disorders, are linked to arrhythmia-related mortality. Despite many efforts to enhance the efficiency of risk-stratification strategies, effective tools for risk assessment are still missing. Biomarkers have a major impact on clinical practice in various cardiac pathologies. While classic biomarkers like brain natriuretic peptide (BNP) and troponins are integrated into daily clinical practice, inflammatory biomarkers may also be helpful for risk assessment. Indeed, several trials investigated their application for the prediction of arrhythmic events indicating promising results. Furthermore, in recent years, active research efforts have brought forward an increasingly large number of "novel and alternative" candidate markers of various pathophysiological origins. Investigations of these promising biological compounds have revealed encouraging results when evaluating the prediction of arrhythmic events. To elucidate this issue, we review current literature dealing with this topic. We highlight the potential of "classic" but also "novel" biomarkers as promising tools for arrhythmia prediction, which in the future might be integrated into clinical practice.

The Lactate/Albumin Ratio: A Valuable Tool for Risk Stratification in Septic Patients Admitted to ICU.

The lactate/albumin ratio has been reported to be associated with mortality in pediatric patients with sepsis. We aimed to evaluate the lactate/albumin ratio for its prognostic relevance in a larger collective of critically ill (adult) patients admitted to an intensive care unit (ICU). A total of 348 medical patients admitted to a German ICU for sepsis between 2004 and 2009 were included. Follow-up of patients was performed retrospectively between May 2013 and November 2013. The association of the lactate/albumin ratio (cut-off 0.15) and both in-hospital and post-discharge mortality was investigated. An optimal cut-off was calculated by means of Youden's index. The lactate/albumin ratio was elevated in non-survivors (p < 0.001). Patients with an increased lactate/albumin ratio were of similar age, but clinically in a poorer condition and had more pronounced laboratory signs of multi-organ failure. An increased lactate/albumin ratio was associated with adverse in-hospital mortality. An optimal cut-off of 0.15 was calculated and was associated with adverse long-term outcome even after correction for APACHE2 and SAPS2. We matched 99 patients with a lactate/albumin ratio >0.15 to case-controls with a lactate/albumin ratio <0.15 corrected for APACHE2 scores: The group with a lactate/albumin ratio >0.15 evidenced adverse in-hospital outcome in a paired analysis with a difference of 27% (95%CI 10-43%; p < 0.01). Regarding long-term mortality, again, patients in the group with a lactate/albumin ratio >0.15 showed adverse outcomes (p < 0.001). An increased lactate/albumin ratio was significantly associated with an adverse outcome in critically ill patients admitted to an ICU, even after correction for confounders. The lactate/albumin ratio might constitute an independent, readily available, and important parameter for risk stratification in the critically ill.